A tumor-intrinsic PD-L1/NLRP3 inflammasome signaling pathway drives resistance to anti-PD-1 immunotherapy
- 1 May 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (5), 2570-2586
- https://doi.org/10.1172/JCI133055
Abstract
An in-depth understanding of immune escape mechanisms in cancer is likely to lead to innovative advances in immunotherapeutic strategies. However, much remains unknown regarding these mechanisms and how they impact immunotherapy resistance. Using several preclinical tumor models as well as clinical specimens, we identified a mechanism whereby CD8(+) T cell activation in response to programmed cell death 1 (PD-1) blockade induced a programmed death ligand 1/NOD-, LRR-, and pyrin domain-containing protein 3 (PD-L1/NLRP3) inflammasome signaling cascade that ultimately led to the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into tumor tissues, thereby dampening the resulting antitumor immune response. The genetic and pharmacologic inhibition of NLRP3 suppressed PMN-MDSC tumor infiltration and significantly augmented the efficacy of anti-PD-1 antibody immunotherapy. This pathway therefore represents a tumor-intrinsic mechanism of adaptive resistance to anti-PD-1 checkpoint inhibitor immunotherapy and is a promising target for future translational research.Keywords
Funding Information
- National Institute of Health (K08 CA191063-04)
- Melanoma Research Alliance (Pilot Grant)
- Merck (Pre-Clinical Research Grant)
- AstraZeneca (Pre-Clinical Research Grant)
- Duke University School of Medicine (Duke University Health Scholar Award)
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